Marijuana is the most commonly abused illicit drug in the US. In recent years, interest has increased in using marijuana and its psychoactive components, the cannabinoids, for symptom relief in specific chronic illnesses. Despite its frequent illicit use,and its potential therapeutic benefits, we are just beginning to understand how cannabinoids produce their actions. The psychoactive effects of marijuana are primarily due to the activation by cannabinoids of a G protein-coupled receptor (CPCR), the CB1 cannabinoid receptor. The immunomodulatory effects of cannabinoids are likely mediated by another GPCR, the CB2 cannabinoid receptor. Despite their importance in determining the effects of cannabinoids, the molecular events associated with activation and regulation of both cannabinoid receptors are incompletely understood. This component of the program project draws on the resources and results of Core 2 and Project 1, combining chemistry, molecular biology and cell biology to understand cannabinoid receptor activation and desensitization in order to provide the insight necessaryto develop therapeutically useful cannabinoid drugs. This proposal focuses on determining how diverse ligands differentially stimulate cannabinoid receptor activation and desensitization and on the role of the cannabinoid receptor oligomerization in this cycle. These studies will be accomplished by completing the following specific aims: 1. To identify cannabimimetic ligands that signal efficiently, yet show little desensitization. 2. To determine the role of the receptor dimerization in CB1<and CB2 receptor signaling. Accomplishing these specific aims will substantially advance our understanding of the mechanisms underlying CB1 and CB2 receptor activation and desensitization. In addition, ligands identified in specific aim 1 will serve as lead compounds in the development of therapeutically useful cannabinoid receptor agonists.